Evaluation of anti-neoplastic effects of NF-kB inhibition by DHMEQ (Dehidroximetilepoxiquinomicina) in medulloblastoma cell lines

Author(s)

Priscila Maria Manzini Ramos

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2014-05-30

Examining board members

Luiz Gonzaga Tone; Oswaldo Keith Okamoto; Rodrigo Alexandre Panepucci; Enilze Maria de Souza Fonseca Ribeiro; Carlos Alberto Scrideli

• Advisor: Luiz Gonzaga Tone

Abstract

Medulloblastoma is a cancer of the central nervous system, highly invasive, of embryonic origin, located in the cerebellum. It is more common among children and accounts for approximately 20% of all pediatric intracranial tumors. The most common treatments are surgery and chemotherapy, and radiotherapy is only to children older than 3 years old due to its side effects. Several studies have demonstrated the role of NF-B in the regulation of genes involved in the neoplastic process. NF-B is a key transcription factor in the regulation of immune response and inflammation process, and it is involved in the transcriptional regulation of a large number of genes related to the tumorigenesis process, and constitutively active in many types of cancer, being an important potential therapeutic target. DHMEQ (Dehidroximetilepoxiquinomicina) is a drug that inhibits the translocation of NF-B from the cytoplasm to the nucleus, thus inhibiting its activity as a transcriptional activator. Several studies have shown the antineoplastic effects of DHMEQ in numerous tumor types, however, there is no surveys that have tested their effects in medulloblastoma. Thus, the present study aimed to evaluate the effects of this drug in UW402, UW473 and ONS-76 pediatric medulloblastoma cell lines through functional and molecular studies. The proliferation test results demonstrated a significant decrease in the cell growth in the medulloblastoma cell lines, inhibiting approximately 80, 70 and 60% for UW402, UW473 and ONS-76, respectively, at a dose of 20g/mL, and showed an IC50 of 10g/mL at 48h for UW402 and UW473 and at 72h in ONS-76. Additionally, increased the level of apoptosis to 50, 17 and 31% in these cell lines, respectively, strongly inhibited the clonogenic capacity, the migration and cell invasion in the three lines and it was synergistic in combination with other chemotherapeutic agents in most combination points, and radiosensitization strongly the three cell lines. The results are congruent with the potential antitumor effect of DHMEQ. (AU)

• FAPESP's process: 10/18792-2 - Evaluation of anti-neoplastic effects of inhibition of NFKB by DHMEQ (Dehydroxymethylepoxyquinomicin) in medulloblastoma cell lines
• Grantee: Priscila Maria Manzini Ramos
• Support Opportunities: Scholarships in Brazil - Doctorate